Urotensin II 수용체 길항제에 의한 혈관증식 억제 효능 및 기전
Inhibitory Effects of Novel Urotensin II Receptor Antagonists on Vascular Smooth Muscle Cell Proliferation.
- 주제(키워드) Urotensin II , Urotensin II receptor , Urotensin II receptor antagonists , Atherosclerosis , ERK , ROS , Proliferation , ligation.
- 발행기관 아주대학교
- 지도교수 정이숙
- 발행년도 2015
- 학위수여년월 2015. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학
- 실제URI http://www.dcollection.net/handler/ajou/000000018896
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cell proliferation and is involved in the pathogenesis of atherosclerosis, restenosis and vascular remodeling. In this study, effects of KR-36676 and KR-36996, a novel selective urotensin receptor (UT) antagonist, on smooth muscle cell proliferation was examined. UII-induced proliferation of human aortic smooth muscle cells (hAoSMCs), was found to be significantly inhibited by KR-36676 and KR-36996 (1, 10, and 100 nM) in dose-dependent manner. UII-induced proliferation of hAoSMCs cells was also inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 and SB202190, inhibitors of JNK and p38 MAPK, respectively. UII increased the phosphorylation of ERK1/2, but this increase was significantly inhibited by KR-36676 and KR-36996. In addition, the UII-induced proliferation was also inhibited by trolox, a scavenger of reactive oxygen species (ROS), while the UII-induced ROS was also decreased in response to KR-36676 and KR-36996 treatment. Moreover, in a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36676 and KR-36996 (30 mg/kg). Taken together, KR-36676 and KR-36996 attenuated UII-induced proliferation of hAoSMCs cells, at least partially, through blocking ERK1/2 activation and ROS generation.
more목차
Abstract i
TABLE OF CONTENTS iii
LIST OF FIGURES v
ABBREVIATION vi
Ⅰ. INTRODUCTION 1
A. Atherosclerosis 1
B. Urotensin II 1
C. Antagonists 2
D. Aims 2
Ⅱ. MATERIALS AND METHODS 3
A. Chemicals and Reagents 3
B. Cell culture 3
C. 5-bromo-2'-deoxyuridine (BrdU) incorporation 4
D. Western blotting 4
E. Measurements of reactive oxygen species (ROS) release 5
F. Mouse carotid ligation model 5
G. Hematoxylin and eosin staining 6
H. Statistical analysis 7
Ⅲ. RESULTS 8
A. Effect of KR-36676 and KR-36996 on SMC proliferation. 8
B. Inhibitory of inhibitors on UII-induced proliferation in hAoSMCs. 10
C. UII-induced ROS generation in HASMC on time course. 11
D. Effect of KR-36676 on UII-induced ROS generation in hAoSMCs. 13
E. Effect of KR-36996 on UII-induced ROS generation in hAoSMCs. 16
F. Effect of KR-36676 on UII-induced ERK activation in hAoSMCs. 18
G. Effect of KR-36996 on UII-induced ERK activation in hAoSMCs. 20
H. Effect of KR-36676 on carotid ligation-induced intimal thickening. 22
I. Effect of KR-36996 on carotid ligation-induced intimal thickening. 24
Ⅳ. DISCUSSION 26
Ⅴ. CONCLUSION 30
REFERENCES 31
국문요약 34
